Single-Cell Map Reveals Epigenomic Regulation of Human Fat Tissue

A new study has created the first single-cell map of how DNA is regulated and organized inside different cell-types of human fat tissue. The research shows that many genetic risk factors for abdominal obesity reside in epigenomic regions of fat cells, offering clues about how body fat is genetically and epigenetically regulated and how it might be better controlled. The study, by co-first authors Zeyuan (Johnson) Chen and Sankha Subhra Das, is published in Nature Genetics.

Why It Matters

Excess belly fat is strongly linked to cardiometabolic diseases like type 2 diabetes and heart disease. While scientists have identified genetic variants associated with the increased risk of these common conditions, it wasn't clear what types of epigenomic regulatory mechanisms drive the risk in cells. This study helps annotate the genome through the lens of epigenomic regulation in fat tissue cell-types, especially in the mature fat cells, shedding light on cell-type level regulatory mechanisms underlying obesity in human fat tissue.

What the Study Did

Researchers analyzed cells isolated from adult fat tissue using single-cell technologies that examine how the DNA strands fold and loop inside the nucleus (3D genome structure) and how methyl groups attach to them (DNA methylation) to turn on or off gene expression. They looked at more than 36,075 individual cells to build a detailed map of expression and epigenomic regulation profiles in different types of cells in fat tissue. They then compared this map with regions known to harbor genetic risk for abdominal obesity.

What They Found

• As adipocytes, the key fat-storing cells, mature, their DNA reorganizes in 3D space. The study reveals the regional architecture of this 3D space throughout the human genome in fat tissue cell-types, pinpointing key regulatory sites of the genome with genes active in adipocytes, such as ADIPOQ, LEP, and SREBF1.
• The investigators found that most known obesity-linked genetic variants are located in the large epigenomic regulatory stretches (megabases in length) of the fat cell chromosomes identified in this study.
• At a finer resolution, these obesity risk variants preferentially reside in shorter spans of DNA loci (hundreds of base pairs), acting like knobs to fine-tune the expression level of genes essential for adipocyte function.

What's Next

Future studies will test whether manipulating those epigenetic marks affects adipocyte behavior in vitro or in animal models. Targeted epigenome editing could validate whether altering methylation or chromatin loops rescues metabolic dysfunction. This unique single-cell epigenome atlas also paves the way for disentangling the epigenomic profiles from fat tissue, elucidating the underlying cellular composition and its links to human disease. In the long term, it can advance precision medicine by facilitating the identification of adipocyte-specific biomarkers and therapies for cardiometabolic diseases, all tailored to an individual's unique genomic and epigenomic signature.

From the Experts

"By working at single-cell resolution, we can pinpoint the cell types where obesity risk is written in the epigenome," said the study's corresponding author Paivi Pajukanta, MD, PhD, professor of Human Genetics at the David Geffen School of Medicine at UCLA. "This gives us an epigenomic roadmap for functionally studying how genetic risk of obesity impacts fat cell biology."